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ERBB1 Is Amplified and Overexpressed in High-grade Diffusely Infiltrative Pediatric Brain Stem Glioma¹

Brain Tumor Program [R. J. G., A. H., R. H., A. G.] and Department of Biostatistics [M. K., L. R.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105; Children’s Hospital and Regional Medical Center, Seattle, Washington 98105-0371 [R. G., J. O.]; Departments of Neurosurgery [I. F. P.] and Pathology [R. L. H., S. D. F.], University of Pittsburgh Medical Center and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213

Purpose: This study was conducted to investigate the incidence of ERBB1 amplification and overexpression in samples of diffusely infiltrative (WHO grades II–IV) pediatric brain stem glioma (BSG) and determine the relationship of these abnormalities to expression and mutation of TP53 and tumor grade.

Experimental Design: After central pathology review, the incidence of ERBB1 amplification and overexpression was determined in 28 samples (18 surgical biopsy and 10 postmortem specimens) of BSG using quantitative PCR and immunohistochemistry, respectively. Mutation and expression of TP53 were also determined in these same samples by direct sequence analysis of microdissected tumor material and immunohistochemistry, respectively. All experimental procedures were performed blind to tumor grade.

Results: Twelve, 9, and 7 tumors were classified as WHO grades II, III, and IV, respectively. A significant increase in ERBB1 expression was observed with increasing tumor grade (P < 0.001). Two grade IV tumors displayed intense membranous ERBB1 expression in 90% of tumor cells in association with high-level ERBB1 gene amplification. One grade III tumor also contained low-level amplification of ERBB1. Six tumors demonstrated TP53 nuclear immunoreactivity, and six contained a mutation in TP53. No correlation was observed between abnormalities in TP53 and either tumor grade or amplification and overexpression of ERBB1.

Conclusions: These data suggest that ERBB1 signaling is important for the development of childhood BSG and is worthy of study as a therapeutic target in this disease. Our data also indicate that the genetics of childhood BSG are complex and include both grade-dependent amplification and overexpression of ERBB1 and grade-independent expression and mutation of TP53.

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